This is a revised application for Project by Jernigan. During the previous funding period, we defined and contrasted the patterns of HIV- and METH-related brain structural alterations. Striatal and parietal cortex volumes are increased in METH (possibly related to strong microglial and astrocytic activation), while there are widespread volume losses in HIV (probably reflecting greater neural damage associated with neurotoxic viral products). Importantly, specific damage in caudate nucleus is associated with HIV, and disproportionate effects in parietal cortex associated with METH. We focus here on the implications of these changes for cognitive-motor processing, and hypothesize that the METH-related parietal lobe alterations (previously unexplored) interact with striatal changes and produce disproportionate attentional deficits. The major aim of the project is to establish links between the structural alterations and the neuromotor and neurocognitive deficits present in HIV and METH. The studies are driven by specific hypotheses about the roles that the distinct neural alterations of HIV and METH play in producing neuromotor and neurocognitive deficits. Combining multimodal imaging with sophisticated neurobehavioral and biomarker indices, we will study the following age- and education-matched groups: HIV-/METH-, HIV-/METH+, HIV+/METH-, and HIV+/METH+. Because we have observed structural alterations associated with each risk factor, we will determine whether baseline perfusion abnormalities exist in the structures affected by HIV and/or METH. Arterial spin labeling (ASL) methods will be used to measure baseline perfusion. To test hypotheses about HIV-related and METH-related neurocognitive and nueromotor impairment, BOLD effects will be obtained using 2 activation paradigms expected to elicit different (impaired) responses in the two risk groups: responsive motor switching (RMS) and global/local divided attention (Glo/Loc). The findings of these studies will advance the understanding of manifestations and mechanisms of neural abnormalities associated with HIV and METH.